Nephrotic patients frequently have suppressed immune responsiveness. The overall goal of this project is to characterize the immunologic abnormality in nephrosis in order to examine its relationship to renal disease. In the initial three year funding period, we detected and partially purified the lymphokine soluble immune response suppressor (SIRS) from urine of patients with steroid-responsive nephrotic syndrome. Like albuminuria in these patients, production of SIRS in inhibited by corticosteroids. Since SIRS injected in mice causes immune suppression similar to that often observed in nephrotic patients, these data suggest that the causes of immune suppression and nephrosis may, indeed, be related. The first aim of this competing renewal application is to continue characterizing SIRS produced by nephrotic patients. To accomplish this aim, purification of urine SIRS will be completed. The purified protein will be compared to SIRS purified from cellular sources by peptide mapping, amino acid composition and carbohydrate content. Physical properties of urine and serum SIRS from the same patient will be compared to evaluate renal handling of SIRS. The second specific aim is to characterize a substance found in serum of steroid-responsive nephrotic patients which activates normal lymphocytes to produce SIRS. Preliminary data suggest that this agent is a protein which is antigenically distinct from SIRS. The serum SIRS-inducing factor will be compared and contrasted with other immunosuppressive agents both antigenically and functionally. Serum from steroid- responsive nephrotic patients will be fractionated by gel filtration, reverse-phase high pressure liquid chromatography and isoelectric focusing to achieve preliminary physical characterization of the SIRS- inducing factor. Finally, efforts will be made to determine the origin of this factor in nephrotic patients and to find methods for obtaining large quantities of this factor for purification. Identification of a mechanism for suppressor cell activation in steroid-responsive nephrosis may help clarify the relationship between suppressed immunity and the pathogenesis of nephrotic proteinuria.